(a) Field of the Invention
The present invention relates to diblock copolymers and more particularly to polycaprolactone-b-polyethylene oxide (PCL-b-PEO) diblock copolymers used in micellar systems.
(b) Description of Prior Art
Colloidal drug delivery vehicles such as liposomes, microspheres, nanospheres and block copolymer micelles increase the therapeutic index and improve the selectivity of various potent drugs (Gregoriadis G., (1995) TIBS, 13:527-537; Muller R. H., (1991) Colloidal Carriers for Controlled Drug Delivery and Targeting: Modification, Characterization and In vivo Distribution, CRC Press Inc., Florida; Kabanov A. V., Alakhov V. Y. (1997) xe2x80x9cMicelles of Amphiphilic Block Copolymers as Vehicles for Drug Deliveryxe2x80x9d In Amphiphilic Block Copolymers: Self-Assembly and Applications edited by Alexamdris P., Lindman B., Elsevier, Netherlands; Kwon G. et al. (1997) J. Controlled Release, 48:195-201; La S. B. et al. (1996) Journal of Pharmaceutical Sciences, 85:85-90; Kataoka K. et al. (1992) J. Control. Release, 24:119-132). These vehicles optimize the therapeutic efficacy of drugs by preventing their rapid elimination from the body, reducing their systemic toxicity, delaying their degradation and optimizing their metabolism (Muller R. H., (1991) Colloidal Carriers for Controlled Drug Delivery and Targeting: Modification, Characterization and In vivo Distribution, CRC Press Inc., Florida; Kabanov A. V., Alakhov V. Y. (1997) xe2x80x9cMicelles of Amphiphilic Block Copolymers as Vehicles for Drug Deliveryxe2x80x9d In Amphiphilic Block Copolymers: Self-Assembly and Applications edited by Alexamdris P., Lindman B., Elsevier, Netherlands). In addition, they also provide for effective delivery of drugs to specific target sites (Muller R. H., (1991) Colloidal Carriers for Controlled Drug Delivery and Targeting: Modification, Characterization and In vivo Distribution, CRC Press Inc., Florida) and aid in overcoming both transport limitations and defense mechanisms associated with the multi-drug resistance phenotype.
It is known to use micellar systems formed from block copolymers in drug delivery (Kabanov A. V., Alakhov V. Y. (1997) xe2x80x9cMicelles of Amphiphilic Block Copolymers as Vehicles for Drug Deliveryxe2x80x9d In Amphiphilic Block Copolymers: Self-Assembly and Applications edited by Alexamdris P., Lindman B., Elsevier, Netherlands; Kwon G. et al. (1997) J. Controlled Release, 48:195-201; La S. B. et al. (1996) Journal of Pharmaceutical Sciences, 85:85-90; Kataoka K. et al. (1992) J. Control. Release, 24:119-132; Bader H., Ringsdorf H., Schmidt B., (1984) Angewandte Makromolekulare Chemie, 123:457-485). Copolymers are formed from two or more monomeric units which, following polymerization, are arranged in a specific manner depending on the type of copolymer desired. Block copolymers consist of a block or sequence of one repeat unit coupled to a block of another repeat unit.
Micelles are formed from individual block copolymer molecules, each of which contains a hydrophobic block and a hydrophilic block. The amphiphilic nature of the block copolymers enables them to self-assemble to form nanosized aggregates of various morphologies in aqueous solution such that the hydrophobic blocks form the core of the micelle, which is surrounded by the hydrophilic blocks, which form the outer shell (Zhang L. Eisenberg A. (1995) Science, 268:1728-1731; Zhang L, Yu K., Eisenberg A. (1996) Science, 272:1777-1779). The inner core of the micelle creates a hydrophobic microenvironment for the non-polar drug, while the hydrophilic shell provides a stabilizing interface between the micelle core and the aqueous medium. The properties of the hydrophilic shell can be adjusted to both maximize biocompatibility and avoid reticuloendothelial system uptake.
The size of the micelles is usually between 10 nm and 100 nm (Kabanov A. V., Alakhov V. Y. (1997) xe2x80x9cMicelles of Amphiphilic Block Copolymers as Vehicles for Drug Deliveryxe2x80x9d In Amphiphilic Block Copolymers: Self-Assembly and Applications edited by Alexamdris P., Lindman B., Elsevier, Netherlands). This size is small enough to allow access to small capillaries while avoiding reticuloendothelial system uptake (Kabanov A. V., Alakhov V. Y. (1997) xe2x80x9cMicelles of Amphiphilic Block Copolymers as Vehicles for Drug Deliveryxe2x80x9d In Amphiphilic Block Copolymers: Self-Assembly and Applications edited by Alexamdris P., Lindman B., Elsevier, Netherlands). Micelles in this size range are also large enough to escape renal filtration, which increases their blood circulation time.
Existing block copolymer micelle systems are based on polyethylene oxide-b-polypropylene oxide-b-polyethylene oxide triblock copolymer or on block copolymers which have a polypeptide or polylactic acid core-forming block and a polyethylene oxide block which forms the hydrophilic corona (Kabanov A. V., Alakhov V. Y. (1997) xe2x80x9cMicelles of Amphiphilic Block Copolymers as Vehicles for Drug Deliveryxe2x80x9d In Amphiphilic Block Copolymers: Self-Assembly and Applications edited by Alexamdris P., Lindman B., Elsevier, Netherlands; Kwon G. et al. (1997) J. Controlled Release, 48:195-201; La S. B. et al. (1996) Journal of Pharmaceutical Sciences, 85:85-90; Kataoka K. et al. (1992) J. Control. Release, 24:119-132).
Polycaprolactone and polyethylene oxide are used in a variety of biomedical applications (Elbert D. L., Hubbell J. A., (1996) Annu. Rev. of Mater. Sci., 26:365-394; Lee J. H. et al. (1995) Prog. Polym. Sci., 20:1043-1079). Polycaprolactone is a synthetic semicrystalline biodegradable polymer that, due to its biodegradability, has been tried both as a structural material in the production of medical devices such as implants, sutures, stents and prosthetics, and as a carrier for a variety of drugs. Polycaprolactone pastes have been developed as a drug delivery system for the anti-cancer agent taxol and the anti-neoplastic agent bis(maltolato)oxovanadium. Nanoparticle, nanocapsule and microparticle drug carriers made of polycaprolactone have been assayed for the ocular delivery of indomethacin. Polyethylene oxide is commonly used to impart blood compatibility to a material surface (Elbert D. L., Hubbell J. A., (1996) Annu. Rev. of Mater. Sci., 26:365-394; Lee J. H. et al. (1995) Prog. Polym. Sci., 20:1043-1079).
Triblocks of polycaprolactone-b-polyethylene oxide-b-polycaprolactone (PCL-b-PEO-b-PCL) have been used to form tablets. Matrices to be used as implants for drug delivery systems have been formed from PCL6-b-PEO90-b-PCL6.
The use of diblock copolymer micelles of methoxy poly(ethylene glycol) and xcexa3-caprolactone as a drug delivery system is known.
The transport of a biologically active agent to a specific site requires a vehicle which is properly armed to confront the many obstacles or barriers it will face within the body. For this, the drug carrier must be tailor-made to suit a particular application. For example, drug accessibility to the central nervous system (CNS) is limited by the blood-brain barrier and major obstacles to delivering drugs to the CNS include the biocompatibility of the materials used and a control of the release kinetics of the drug delivery system used. There lacks an adequate means of long-term delivery to the CNS.
The FK506 drug, otherwise known as tacrolimus or Prograf(trademark), has been effectively used to achieve immunosuppression in organ transplant recipients. FK506 binds to the immunophilin FKBP12 to form a complex which binds to and inhibits calcineurin; this, in turn, results in immunosuppression. FK506 promotes neuronal outgrowth in terms of the enhancement of neurite extension in PC 12 (rat pheochromocytoma) cell cultures and explant cultures of rat sensory ganglia. However, the use of FK506 for the treatment of neurodegenerative diseases is limited by its immunosuppressant activity.
At present, FK506 is administered either orally, in a capsule, or by injection as a sterile solution. A microemulsion formulation of FK506 has also been developed.
L-685,818 is a structural analogue to FK506. L-685,818 has retained the neurotrophic action of FK506 but has lost its immunosuppressant action. The structural difference between FK506 and L-685,818 is in the addition of a hydroxyl group on the analogue at C-18 and the substitution of an ethyl group for an allyl group at C-21. L-685,818 is of interest for its potential use in the treatment of neurodegenerative diseases, as it enhances functional and morphologic recovery in rats with crushed sciatic nerves.
Various approaches have been developed to provide continuous delivery of biologically active agents such as neuroactive agents, and, although these have overcome some of the problems of delivering the agents, numerous problems remain such as the linearity of release, the biocompatibility of the materials used and the loading capacity.
It would therefore be highly desirable to be provided with polycaprolactone blocks, which would create a larger hydrophobic microreservoir, enabling the incorporation of a greater amount of biologically active agents while preventing damaging effects that such an amount would induce.
One aim of the present invention is to provide polycaprolactone blocks for obtaining a hydrophobic microreservoir and enabling an amount of lipophilic active agent to be incorporated in a micellar system constructed with such blocks, with a slower release and without the damaging effect that such high doses would induce compared to known delivery systems. Control over the degree of incorporation and the release kinetics may then be gained by varying the length of the polycaprolactone block used in the micellar system.
Another aim of the present invention is to provide a block copolymer micellar system, formed from polycaprolactone-b-polyethylene oxide (PCL-b-PEO) diblocks for delivering a biologically active agent to a specific site.
Polycaprolactone polyethylene oxide blocks are used to form micelles smaller than those of the prior art and more efficient as a drug delivery system for biologically active agents.
In accordance with one aspect of the present invention, there is provided a diblock copolymer compound comprising a hydrophilic block and a hydrophobic block, the hydrophilic block comprising a polyethylene oxide polymer, and the hydrophobic block comprising a polycaprolactone polymer, the polycaprolactone polymer comprising a number of caprolactone monomers selected from 5 to 150, the polyethylene oxide polymer comprising a number of ethylene oxide units monomers selected from 20 to 100.
The number of ethylene oxide monomers may be selected from 20 to 80.
The number of ethylene oxide monomers may be selected from 30 to 60.
The selected number of caprolactone monomers may be 14 and the selected number of ethylene oxide monomers may be 44.
The selected number of caprolactone monomers may be 20 and the selected number of ethylene oxide monomers may be 44.
In accordance with yet another aspect of the present invention, there is provided a diblock copolymer micellar system comprising a plurality of such diblock copolymers, wherein the diblock copolymers are assembled in a suitable aqueous medium such that the hydrophobic blocks define a core of the micellar system and the hydrophilic blocks define a shell surrounding the core.
The micellar system may have a diameter varying essentially from about 10 nanomers to about 100 nanometers.
The micellar system may contain a biologically active agent into the core.
The biologically active agent may be lipophilic.
The biologically active agent may consist of a neuroactive agent.
The neuroactive agent may be selected from the group consisting of FK506 and L-685,818.
The neuroactive agent may consist of L-685,818.
In accordance with yet another aspect of the present invention, there is provided a composition comprising a population of such micellar systems in combination with a suitable carrier.
The copolymers may be present in a solution in an amount selected from about 0.5% to 3% by weight.
In accordance with yet another aspect of the present invention, there is provided a delivery system for delivering a biologically active agent in situ in a patient. The delivery system comprises a plurality of such micellar systems.
The in situ delivery may be effected to the central nervous system of a patient.
In accordance with yet another aspect of the present invention, there is provided a method for preparing such a population of micellar systems. The method comprises dissolving such copolymers in a suitable organic solvent solution and adding water in a dropwise fashion to the solution to form the micellar systems.
The organic solvent solution may be a DMF solution.
The amount of drug incorporated in the micelle and the release kinetics of that drug are largely a function of the interaction between the drug and the core-forming block. Since polycaprolactone is more hydrophobic than other polymers commonly used as core-forming blocks (e.g. polypropylene oxide), this system may have a larger capacity for the most hydrophobic drugs.
The polycaprolactone micellar core is suitable for the incorporation of a variety of biologically active agents including, without limitation, neutral, lipophilic drugs.
Examples of biologically active agents include, without limitation, nonpolar, lipophilic drugs, vitamins, immunosuppressants, immunoactive agents, neutraceuticals, peptidomimetics mimicking growth factors and their antagonists and immunomodulator agents.
The micellar system of the present invention is also suitable to the cosmetic industry such as in the delivery of active agents in creams, toiletries, deodorants, skin and sunscreen preparation. The micellar system of the present invention is also useful in perfumes, by stabilizing the unstable components thereof and by controlling the release kinetics of the fragrance upon application.
The release kinetics of the micelles can be made to vary by changing a range of parameters, including the nature of the copolymer employed, the length of the individual polymer blocks and the morphology and size of the micelles. The morphology and effective diameter of the micelles is controlled by varying specific parameters during micelle preparation.